Richetin K, Steullet P, Pachoud M, Perbet R, Parietti E, Maheswaran M, Eddarkaoui S, Bégard S, Pythoud C, Rey M, Caillierez R, Q Do K, Halliez S, Bezzi P, Buée L, Leuba G, Colin M, Toni N, Déglon N. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer's disease. Nat Neurosci. 2020 Dec;23(12):1567-1579. Epub 2020 Nov 9 PubMed.

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  1. In this important study, Richetin et al. demonstrate that astrocytes in the hilus of the hippocampus dentate gyrus accumulate misfolded 3R-tau in Alzheimer’s disease (AD). Using an elegant lentiviral gene transfer approach in vivo (wild-type mice) and in vitro (rat hippocampal neuron/astrocyte co-cultures and mouse acute hippocampal slices), they studied the downstream effects of this tau accumulation in hilar astrocytes and observed multiple phenotypes in both astrocytes and neurons when overexpressing 1N3R-tau in astrocytes: impairment to astrocyte mitochondrial transport, to REDOX and ATP production, as well as to calcium homeostasis; reduced maturation of newborn neurons in the subgranular zone of the dentate gyrus; structural synaptic alterations involving excitatory and inhibitory synapses; loss of inhibitory parvalbumin-positive neurons, and impaired hippocampal circuit γ oscillations and spatial memory.

    These findings highlight the astrocyte cell-autonomous and non-cell-autonomous consequences in the setting of neurodegenerative proteinopathies, and support the idea that the biology of reactive astrocytes, not just neurons, is negatively impacted by protein aggregates in AD and other tauopathies, leading to further neuronal dysfunction.

    Some questions remain to be elucidated. Is tau expression increased in AD-reactive astrocytes or is it taken up from the extracellular space by astrocytes after being released by neurons? Astrocytes express very low levels of MAPT, encoding the microtubule-associated protein tau, compared to neurons in the normal brain (Zhang et al., 2016). Recent single-nuclei RNA-Seq studies have not reported increased levels of MAPT transcripts in AD-reactive astrocytes (Mathys et al., 2019; Grubman et al., 2019; Zhou et al., 2020). However, tau-immunoreactive astrocytes can be found in the brains of otherwise normal aged individuals and more frequently in subjects with AD and other neurodegenerative diseases, with granular fuzzy and thorn-shaped morphologies, and within subpial, perivascular, subependymal, white-matter and gray-matter areas, including the medial temporal lobe (Lace et al., 2012; López-González et al., 2012)—collectively called Aging-Related Tau Astrogliopathy, or ARTAG (Kovacs et al., 2017). 

    In addition, tau-immunoreactive astrocytes are pathological hallmarks of the primary tauopathies progressive supranuclear palsy and corticobasal degeneration, which exhibit tufted astrocytes and astrocytic plaques, respectively (Dickson et al., 1999), and they are also conspicuous in chronic traumatic encephalopathy (CTE) (McKee et al., 2016). Intriguingly, the astrocytic tau inclusions described in all these conditions contain primarily 4R-tau rather than 3R-tau. It is unclear why 3R-tau staining was more prominent than 4R-tau in the hilar astrocytes of this study's subjects, and why the accumulation of 3R-tau was more deleterious than that of 4R-tau for both astrocytes and neurons.

    What is the mechanism of tau uptake by astrocytes? Neurofibrillary tangles develop primarily in glutamatergic pyramidal neurons and misfolded tau is thought to propagate through neural circuits trans-synaptically. Astrocyte fine processes rich in glutamate transporters are a structural and functional part of the excitatory glutamatergic synapses (Ventura and Harris, 1999). Thus, it is plausible that astrocytes, which are phagocytic cells, take up misfolded tau released by neurons at excitatory synapses. In addition, reactive astrocytes actively infiltrate extracellular “ghost” tangles with their processes (Serrano-Pozo et al., 2011; Irwin et al., 2012; Perez-Nievas and Serrano-Pozo, 2018), and can phagocytose amyloid-plaque-associated neuritic dystrophies (Gomez-Arboledas et al., 2018), which contain tau aggregates. Recently, the low-density lipoprotein related protein 1 (LRP1) has been involved in tau uptake by neurons (Rauch et al., 2020), but LRP1 is also highly expressed in astrocytes among other cell types, and upregulated in AD-reactive astrocytes (Arélin et al., 2002). Indeed, knocking down LRP1 specifically in neurons reduced trans-synaptic tau propagation through neural circuit but increased tau uptake by astrocytes (Rauch et al., 2020). 

    In summary, Richetin et al.’s data show that there are profound synergies between astrocytes and neurons in the pathophysiology of AD and other tauopathies, and suggest that a deeper understanding of astrocytic alterations may prove to be critical in understanding neurodegeneration.

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    Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, Edwards MS, Li G, Duncan JA 3rd, Cheshier SH, Shuer LM, Chang EF, Grant GA, Gephart MG, Barres BA. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron. 2016 Jan 6;89(1):37-53. Epub 2015 Dec 10 PubMed.

    Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai LH. Author Correction: Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019 Jul;571(7763):E1. PubMed.

    Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C, Simmons RK, Buckberry S, Vargas-Landin DB, Poppe D, Pflueger J, Lister R, Rackham OJ, Petretto E, Polo JM. A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation. Nat Neurosci. 2019 Dec;22(12):2087-2097. PubMed.

    Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, Poliani PL, Cominelli M, Grover S, Gilfillan S, Cella M, Ulland TK, Zaitsev K, Miyashita A, Ikeuchi T, Sainouchi M, Kakita A, Bennett DA, Schneider JA, Nichols MR, Beausoleil SA, Ulrich JD, Holtzman DM, Artyomov MN, Colonna M. Author Correction: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nat Med. 2020 Jun;26(6):981. PubMed.

    Lace G, Ince PG, Brayne C, Savva GM, Matthews FE, de Silva R, Simpson JE, Wharton SB. Mesial Temporal Astrocyte Tau Pathology in the MRC-CFAS Ageing Brain Cohort. Dement Geriatr Cogn Disord. 2012;34(1):15-24. PubMed.

    López-González I, Carmona M, Blanco R, Luna-Muñoz J, Martínez-Mandonado A, Mena R, Ferrer I. Characterization of Thorn-Shaped Astrocytes in White Matter of Temporal Lobe in Alzheimer's Disease Brains. Brain Pathol. 2012 Aug 13; PubMed.

    Kovacs GG, Robinson JL, Xie SX, Lee EB, Grossman M, Wolk DA, Irwin DJ, Weintraub D, Kim CF, Schuck T, Yousef A, Wagner ST, Suh E, Van Deerlin VM, Lee VM, Trojanowski JQ. Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases. J Neuropathol Exp Neurol. 2017 Apr 1;76(4):270-288. PubMed.

    Dickson DW. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol. 1999 Sep;246 Suppl 2:II6-15. PubMed.

    McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O'Connor K, Alvarez VE, Gordon WA, TBI/CTE group. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 2016 Jan;131(1):75-86. Epub 2015 Dec 14 PubMed.

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    Arélin K, Kinoshita A, Whelan CM, Irizarry MC, Rebeck GW, Strickland DK, Hyman BT. LRP and senile plaques in Alzheimer's disease: colocalization with apolipoprotein E and with activated astrocytes. Brain Res Mol Brain Res. 2002 Jul 15;104(1):38-46. PubMed.

    View all comments by Bradley Hyman

  2. This is a very interesting study that highlights the susceptibility of astrocytes to preferentially acquire pathological features in the form of confirmation-specific isoforms of tau in hippocampal regions burdened by Alzheimer pathology.

    Seeking to understand the functional consequence of astrocytes burdened by 3R tau, the authors demonstrate that viral-driven expression of the 3R isoform alters mitochondrial transport. Similar anterograde disruptions in the axonal movement of APP were observed in neuronal cultures when the balance of 3R:4R tau was manipulated (Lacovich et al., 2017). 

    Here, Richetin et al.  demonstrate that driving astrocyte-specific expression of 3R in wild-type C57BL6/J mice is sufficient to drive dysfunctional responses of interneurons,  manifesting as cognitive deficits. Given that the wild-type mouse expresses only the 4R confirmation in the adult brain, compared to equimolar distribution of 3R:4R in humans (Andreadis 2005), it would be interesting to know whether these approaches drove the same manifestations in mouse models with humanized MAPT.

    Further, whether accumulation of 4R tau in astrocytes is sufficient to alter neuronal and cognitive dysfunction was not fully elaborated in the current work. Such studies would provide potential mechanistic or dysfunctional underpinnings of astrocytes that acquire predominantly 4R confirmations, as has been documented for ARTAG (Kovacs 2016). 

    View all comments by Josh Morganti

  3. This elegant study by Richetin and colleagues has several interesting and important findings.

    In human participants with Alzheimer's disease, 3R tau accumulation was observed in astrocytes in the hippocampus, specifically the hilus of the dentate gyrus. The amount of 3R (but not 4R) tau in hilar astrocytes was positively correlated with Braak stage, amyloid burden, and synaptic alterations that were specific to the postsynaptic side (increased expression of PSD95).

    Additionally, mouse models convincingly demonstrated that tau pathology in hilar astrocytes (induced via a novel lentiviral vector strategy) led to mitochondrial dysfunction, neurodegeneration, and spatial memory impairment.

    This study builds on previous observations of AD-related tau accumulation in astrocytes by investigating the downstream consequences of this particular pathology, and adds to a growing body of evidence that glial cells are key players in the etiology of AD.

    View all comments by Justin Sanchez

  4. This is a very intriguing and detailed analysis regarding the functional consequences of 3R tau in astrocytes. It is an important reminder that much remains to be learned about the functional consequences of pathological tau in astrocytes. Several older studies have pioneered the study of the consequences of astrocytic tau pathology using mouse models, but to our knowledge this work has never been followed up (Dabir et al., 2006; Forman et al., 2005). 

    We recently presented our findings regarding AAV-mediated viral delivery of truncated tau to astrocytes at AAIC Neuroscience Next 2020. In that study, we expressed human truncated tau (aa151-391/4R)—which we have previously shown to lead to neurofibrillary tangles in neurons (Vogels et al., 2020)—along with non-fused mCherry in a 1:1 ratio under the astrocytic GFAP promotor. In contrast to the study by Richetin and colleagues, we decided to focus on 4R tau, because astrocytic tau pathology in primary tauopathies is almost exclusively associated with accumulation of 4R tau (Kovacs, 2020). 

    At five months after injection in hippocampi of wild-type mice, we found widespread transduction of astrocytes in all subregions of the hippocampus and overlying cortex. We also observed accumulation of p-tau S214 and T231 in astrocytes, but no AT8+ or Methoxy-XO4+ inclusions. No detectable cognitive deficits were observed in open field, novel object recognition, and Y-maze spontaneous alterations tests. At five months after AAV injection in cortex, we also did not detect alterations in neuronal activity in the vicinity of truncated tau positive astrocytes (as visualized with mCherry co-expression) using in vivo 2-photon calcium imaging.

    More studies are therefore required to elucidate the effects of different tau species on astrocytes, the origins of tau in astrocytes, and the multitude of potential functional consequences of astrocytic tau pathology, e.g. on the vasculature.

    References:

    Dabir DV, Robinson MB, Swanson E, Zhang B, Trojanowski JQ, Lee VM, Forman MS. Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J Neurosci. 2006 Jan 11;26(2):644-54. PubMed.

    Forman MS, Lal D, Zhang B, Dabir DV, Swanson E, Lee VM, Trojanowski JQ. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci. 2005 Apr 6;25(14):3539-50. PubMed.

    Kovacs GG. Astroglia and Tau: New Perspectives. Front Aging Neurosci. 2020;12:96. Epub 2020 Apr 9 PubMed.

    Vogels T, Vargová G, Brezováková V, Quint WH, Hromádka T. Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice. J Alzheimers Dis. 2020;77(2):551-568. PubMed.

    View all comments by Thomas Vogels

  5. A recent study in Nature finds that microglia sense ATP and then inhibit neuronal activity (Badimon et al., 2020). Thus, if there is less ATP production by astrocytes then maybe there is also less inhibition by microglia? Additionally, another new Nature paper finds that astrocytes control excitatory and inhibitory synapses (Takano et al., 2020).

    References:

    Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A, Hwang P, Chan AT, Graves SM, Uweru JO, Ledderose C, Kutlu MG, Wheeler MA, Kahan A, Ishikawa M, Wang YC, Loh YE, Jiang JX, Surmeier DJ, Robson SC, Junger WG, Sebra R, Calipari ES, Kenny PJ, Eyo UB, Colonna M, Quintana FJ, Wake H, Gradinaru V, Schaefer A. Negative feedback control of neuronal activity by microglia. Nature. 2020 Oct;586(7829):417-423. Epub 2020 Sep 30 PubMed.

    Takano T, Wallace JT, Baldwin KT, Purkey AM, Uezu A, Courtland JL, Soderblom EJ, Shimogori T, Maness PF, Eroglu C, Soderling SH. Chemico-genetic discovery of astrocytic control of inhibition in vivo. Nature. 2020 Nov 11; PubMed.

    View all comments by Charles Stromeyer

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